Bioequivalence Study of Two Different Formulations of N-acetyl-cysteine (NAC)

Phase 1

Completed

• Conditions: no Condition
• Interventions: Drug: N-acetylcysteine

• Registration Number: NCT02265224
• Lead Sponsor: Zambon SpA

Brief Summary

Study primary Objective:

- To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of N-acetyl-cysteine 600 mg uncoated tablets vs. N-acetyl-cysteine 600 mg film-coated tablets (NAC) in healthy male and female volunteers.

Study secondary objectives:

* To describe the pharmacokinetic (PK) profile of NAC in plasma after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets;

* to collect safety and tolerability data after single dose administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets.

Detailed Description

This is single centre, single dose, open, randomised, cross-over, two-stage bioequivalence study to compare two different oral formulations of NAC.

The study has been conducted in healthy volunteers of both genders, in one single dose of both formulations.

The initial 48 subjects were sufficient to satisfy the study objectives on the basis of the ad interim preliminary bioequivalence test. The study was then considered as concluded and the second stage did not take place.

Study Timeline

• Study Start: 2014-09
• Primary Completion: 2014-09
• Study Completion: 2014-09
• Study First Submitted: 2014-10-03
• Study First Submitted QC: 2014-10-09
• Study First Posted: 2014-10-15
• Status Verified: 2021-10
• Results First Submitted: 2021-10-06
• Results First Submitted QC: 2021-10-06
• Last Update Submitted: 2021-10-06
• Results First Posted: 2021-11-05
• Last Update Posted: 2021-11-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

1. Informed consent: signed written informed consent before inclusion in the study

2. Sex and age: males and females,18-55 years old, inclusive

3. Body Mass Index (BMI): 18.5-30 kg/m2, inclusive

4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, heart rate (HR) 50-90 bpm, measured after 5 min of rest in the sitting position

5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study

6. Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must be using at least one of the following reliable methods of contraception:

   • Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
   • A non-hormonal intrauterine device or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit
   • A male sexual partner who agrees to use a male condom with spermicide
   • A sterile sexual partner Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted.

For all female subjects, pregnancy test result must be negative at screening (serum β-HCG test) and day -1 (urine test).

Exclusion Criteria

1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study
6. Medications: medications, including over the counter (OTC) medications and herbal remedies for 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed
7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
8. Blood donation: blood donations for 3 months before this study
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010], caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day)
10. Drug test: positive result at the drug test at screening or day-1
11. Alcohol test: positive alcohol breath test at day -1
12. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Test - Reference	N-acetylcysteine	N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose)
Reference - Test	N-acetylcysteine	N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose)

Primary Outcome Measures

Name	Time	Method
Cmax of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	Cmax is the maximum concentration level of the drug reached in plasma.
AUC0-t of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.

Secondary Outcome Measures

Name	Time	Method
AUC0-∞ of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.
Tmax of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	time to achieve the maximum concentration level of the drug in plasma.
t1/2 of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	Half-life (t1/2) is the time to halve the plasma concentration level of the drug.
Frel of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Lambda Zeta of NAC After Single Dose Administration of Test and Reference	0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)	Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.